Esomeprazole (Nexium):
A New Proton Pump Inhibitor

Introduction

In 1989, the FDA approved the first proton pump inhibitor (PPI) in the United States, omeprazole (Prilosec™). Lansoprazole (Prevacid®) was the second FDA-approved PPI in 1995, followed by rabeprazole (Aciphex™) in 1999 and pantoprazole (Protonix®) in 2000. Esomeprazole (Nexium™) received FDA-approval in 2001 and is the S-isomer of omeprazole.

Indications

Esomeprazole is FDA-approved for the treatment of symptomatic gastroesophageal reflux disease (GERD), short-term treatment of erosive esophagitis, and maintenance of erosive esophagitis healing. It is also approved for use with antibiotics for the treatment of Helicobacter pylori-associated duodenal ulcers. See Table 1

Clinical Pharmacology

Esomeprazole works by binding irreversibly to the H+/K+ ATPase in the proton pump. Because the proton pump is the final pathway for secretion of hydrochloric acid by the parietal cells in the stomach, its inhibition dramatically decreases the secretion of hydrochloric acid into the stomach and alters gastric pH. This is the same mechanism of action as omeprazole and the other PPIs.

Pharmacokinetics

(See Table 2) Esomeprazole is the S-isomer of omeprazole. It must be administered using an enteric-coated formulation, which delays release of the drug to the alkaline portion of the gastrointestinal tract. Peak plasma concentrations occur 1.56 to 2.3 hours after oral administration on an empty stomach. Esomeprazole is eliminated from the body by hepatic metabolism to inactive metabolites. Hepatic metabolism is performed by the cytochrome P-450 system, specifically the isoenzymes CYP2C19 (73%) and CYP3A4 (27%). Less than 1% of esomeprazole is excreted unchanged in the urine, with 80% excreted renally and the remainder excreted in the feces. The elimination half-life of esomeprazole following single-dose oral administration is 0.85 hours. The half-life increases to 1.2 to 1.5 hours after 5 days of oral administration. The volume of distribution of esomeprazole is 16 to 18 L. Alterations in renal function have no effect on esomeprazole's pharmacokinetics, while patients with liver cirrhosis will have a small delay in the time-to-peak plasma concentration (2 vs 1.56 hours). The geometric mean AUC is increased by 76%, and the half-life is increased by 29%. Mild-to-moderate hepatic dysfunction has no effect on the pharmacokinetics of esomeprazole. Severe hepatic dysfunction (Child-Pugh Class C) can increase the AUC and half-life of esomeprazole.

Table 2. Comparison of the Pharmacokinetic Parameters of Various PPIs

Parameter

Esomeprazole

Lansoprazole

Omeprazole

Pantoprazole

Rabeprazole

Bioavailablitiy

90%

80%

30-40%

77%

52%

Acid liable

Yes

Yes

Yes

Yes

Yes

Enteric-coated
formulation

Yes

Yes

Yes

Yes

Yes

Time to peak

1.5 hours

1.7 hours

0.5-3.5 hours

2.5 hours

2-5 hours

Half-life

1.2-1.5 hours

< 2 hours

0.5-1 hour

-1.9 hours

1-2 hours

Excreted unchanged
in
the urine

< 1%

< 1%

0 %

0 %

0 %

Cytochrome
P450 pathway*

CYP2C19,
CYP3A4

CYP3A, CYP2C19

CYP2C9,
CYP2C8,
CYP2C18,
CYP2C19, CYPA3/4,
CYP3A1A2

CYP2C19, CYP3A4

CYP3A, CYP2C19

Protein binding

97%

97%

95%

98%

96.3%

* = predominate pathway
is highlighted in bold

Adverse Reactions

The adverse events associated with esomeprazole therapy are generally similar to those seen with the placebo and omeprazole therapy. This is similar to the previously available PPIs. The most common adverse events reported in the clinical trials were diarrhea, abdominal pain, flatulence, gastritis, nausea, and headache.

Drug-Drug Interactions

Drug interactions reported with omeprazole have included prolonged elimination of diazepam, warfarin, and phenytoin. Isolated reports of changes in elimination have been reported with cyclosporine, disulfiram, and other benzodiazepines. See Table 3. No drug-drug interactions were found between esomeprazole and phenytoin, R-warfarin, quinidine, amoxicillin, oral contraceptives, and clarithromycin. Esomeprazole may interfere with the elimination of other drugs metabolized by CYP2C19. Coadministration of esomeprazole and diazepam results in a 45% reduction in diazepam clearance and increased plasma diazepam levels. Changes in gastric pH can affect the bioavailability of some medications. Examples of medications where the bioavailability of the medication may be decreased with profound and long-lasting inhibition of gastric acid secretion are ketoconazole and iron salts.

Table 3. Drug Interactions
Reported in the Product Labeling of Various PPIs

Dosage and Administration

(See table 4). The recommended dose of esomeprazole is 20 mg or 40 mg once daily for 4 to 8 weeks for the treatment of erosive esophagitis, 20 mg once daily for maintenance of healed erosive esophagitis (studies lasted up to 6 months), 20 mg once daily for symptomatic GERD for 4 weeks, and as part of a 10-day triple drug regimen for eradication of H. pylori infections (the esomeprazole will be given as a single dose). The regimen recommended for the eradication of H. pylori infection is esomeprazole 40 mg once daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily for 10 days. The capsule should be swallowed whole 1 hour before eating. If the patient has difficulty swallowing the capsule, it can be opened and mixed with applesauce and taken immediately. The applesauce should not be hot and should be soft enough to be swallowed without chewing. The pellet should not be chewed or crushed. It may also be mixed with tap water, orange juice, apple juice, or yogurt.